A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia.

AIMS: TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694). METHODS: The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia. RESULTS: No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia. CONCLUSION: TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.

Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study.

The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.

Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson's disease.

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.

Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function.

Although many studies have examined separately the effects of depression and cortisol on cognition, no study has examined their relative or potentially additive effects. Our study simultaneously investigated the contributions of clinical status [major depression (MD) versus psychiatrically healthy controls (HC)] and cortisol on a hippocampal/mediotemporal mediated verbal memory task (Paragraph Recall) and a prefrontal cortex/cingulate mediated executive functioning task (Stroop). Thirty-seven unmedicated nondelusional MDs and 18 HCs underwent psychiatric ratings, hourly assessments of cortisol activity over 24 h, and neuropsychological assessments. Hierarchical multiple regressions indicated a significant effect of cortisol but not of diagnosis on verbal memory. Greater cortisol levels were related to poorer memory performance independent of group. In contrast, a significant interaction between cortisol and diagnosis was found for a color-word index of response inhibition. This interaction suggests that the detrimental effect of elevated cortisol level on this type of executive functioning exists only in the healthy control group but not in MDs. On an Interference score, another measure of response inhibition, cortisol had a significant independent effect, but neither the effects of diagnosis and the interaction attained full significance. Our study suggests that cortisol has an independent effect on verbal memory. Also, our study produced evidence of an interaction between diagnosis and cortisol on response inhibition.

Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder.

Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.

Abnormalities of thalamic volume and shape in schizophrenia.

OBJECTIVE: Postmortem and neuroimaging studies of schizophrenia have reported deficits in the volume of the thalamus and its component nuclei. However, the pattern of shape change associated with such volume loss has not been investigated. In this study, alterations in thalamic volume, shape, and symmetry were compared in subjects with and without schizophrenia. METHOD: T(1)-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects matched for age, gender, race, and parental socioeconomic status. High-dimensional (large-deformation) brain mapping was used to assess thalamic morphology. RESULTS: Significant differences in thalamic volume, deformities of thalamic shape at the anterior and posterior extremes of the structure, and a significant exaggeration of thalamic asymmetry (i.e., left smaller than right) were found in the schizophrenia subjects. After covarying for total cerebral volume, the difference in thalamic volume became insignificant. When information about thalamic shape was combined with previously collected information about hippocampal shape, the discrimination between schizophrenia patients and comparison subjects was improved. CONCLUSIONS: Thalamic volume was smaller than normal in schizophrenia patients, but only proportionate to reductions in reduced total cerebral volume. The presence of changes in thalamic shape and asymmetry suggest greater pathologic involvement of individual nuclei at its anterior and posterior extremes of the thalamic complex.

High-dimensional mapping of the hippocampus in depression.

OBJECTIVE: Abnormalities of the hippocampus may play a role in the pathophysiology of depression, but efforts to identify a structural abnormality in this brain structure among depressed patients have produced mixed results. Previous research may have been limited by exclusive reliance on measures of hippocampal volume. High-dimensional brain mapping is a new analytic method that quantitatively characterizes the shape as well as volume of a brain structure. In this study, high-dimensional brain mapping was used to evaluate hippocampal shape and volume in patients with major depressive disorder and healthy comparison subjects. METHOD: By using magnetic resonance imaging, brain scans were obtained from 27 patients with major depressive disorder and 42 healthy comparison subjects. High-dimensional brain mapping generated a series of 10 variables (components) that represented hippocampal shape, and hippocampal volumes were also computed. Analysis of variance techniques were used to compare depressed patients and comparison subjects on hippocampal shape and volume. RESULTS: While the depressed patients and comparison subjects did not differ in hippocampal volume, there were highly significant group differences in hippocampal shape. The two groups did not overlap on a discriminant function computed from a model comprising the 10 components. The pattern of hippocampal surface deformation in the depressed patients suggested specific involvement of the subiculum. CONCLUSIONS: Patients with major depression may have structural abnormalities of the hippocampus that can be detected by analysis of hippocampal shape but not volume. A specific defect in the subiculum could have widespread effects throughout neurocircuits that appear to be abnormal in depression.

Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping.

OBJECTIVE: Abnormalities of hippocampal structure have been reported in schizophrenia subjects. However, such abnormalities have been difficult to discriminate from normal neuroanatomical variation. High dimensional brain mapping, which utilizes probabilistic deformations of a neuroanatomical template, was used to characterize disease-related patterns of changes in hippocampal volume, shape, and asymmetry. METHOD: T(1)-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects who were similar in age, gender, and parental socioeconomic status. The schizophrenia subjects were clinically stable at the time of assessment. RESULTS: Significant abnormalities of hippocampal shape and asymmetry (but not volume after total cerebral volume was included as a covariate) were found in the schizophrenia subjects. The pattern of shape abnormality suggested a neuroanatomical deformity of the head of the hippocampus, which contains neurons that project to the frontal cortex. The pattern of hippocampal asymmetry observed in the schizophrenia subjects suggested an exaggeration of the asymmetry pattern observed in the comparison subjects. No correlations were found between the magnitude of hippocampal shape and asymmetry abnormality and the severity of residual symptoms or duration of illness. CONCLUSIONS: Schizophrenia is associated with structural deformities of the hippocampus, which suggest a disturbance of the connections between the hippocampus and the frontal cortex. However, the magnitude of these deformities are not related to severity or duration of illness.